This invention relates generally to the field of unimolecular polymeric micelles (UPM); particularly to UPM and their methods of preparation which result in a micelle having an ionizable core; and most particularly to the use of such micelles as carriers for pharmacological constituents; wherein a directed release of said constituents in response to the ionization state induced upon the UPM is realized.
In order to improve the specific delivery of drugs with a low therapeutic index, several drug carriers such as liposomes, microparticles, nano-associates (e.g. polymeric micelles, polyion complex micelles (PICM)) and drug-polymer conjugates have been studied. In recent years, water-soluble supramolecular assemblies such as polymeric micelles and PICM have emerged as promising new colloidal carriers for the delivery of hydrophobic drugs and polyions (e.g. antisense oligonucleotides), respectively.
Polymeric micelles have been the object of growing scientific attention, and have emerged as potential carriers for drugs having poor water solubility because they can solubilize those drugs in their inner core and they offer attractive characteristics such as a generally small size ( less than 300 nm) and a propensity to evade scavenging by the mononuclear phagocyte system.
Micelles are often compared to naturally occurring carriers such as viruses or lipoproteins. All three of these carriers demonstrate a similar core-shell structure that allows for their contents to be protected during transportation to the target cell, whether it is DNA for viruses or water-insoluble drugs for lipoproteins and micelles.
Polymeric micelles seem to be one of the most advantageous carriers for the delivery of poorly water-soluble drugs as reported by Jones and Leroux, Eur. J. Pharm. Biopharm. (1999) 48, 101-111; Kwon and Okano, Adv. Drug Deliv. Rev. (1996) 21, 107-116 and Allen et al. Colloids Surf. B: Biointerf. (1999) 16, 3-27. They are characterized by a core-shell structure. The hydrophobic inner core generally serves as a microenvironment for the solubilization of poorly water-soluble drugs, whereas the hydrophilic outer shell is responsible for micelle stability, protection against opsonization, and uptake by the mononuclear phagocyte system. Pharmaceutical research on polymeric micelles has been mainly focused on copolymers having an AB diblock structure with A, the hydrophilic shell moieties and B the hydrophobic core polymers, respectively. Multiblock copolymers such as poly(ethylene oxide)-poly(propyleneoxide)-poly(ethylene oxide) (PEO-PPO-PEO) (A-B-A) can also self-organize into micelles, and have been described as potential drug carriers. E.g. Kabanov et al., FEBBS Lett. (1989) 258, 343-345. The hydrophobic core which generally consists of a biodegradable polymer such as a poly(xcex2-benzyl-aspartate) (PBLA), poly(D,L-lactic acid) or poly(xcex5-caprolactone), serves as a reservoir for a poorly water-soluble drug, protecting it from contact with the aqueous environment. The core may also consist of a water-soluble polymer, such as poly(aspartic acid) (P(Asp)), which is rendered hydrophobic by the chemical conjugation of a hydrophobic drug, or is formed through the association of two oppositely charged polyions (PICM). Several studies also describe the use of poorly or non-biodegradable polymers, such as polystyrene (PSt) or poly(methyl methacrylate)(PMMA), as constituents of the inner core. See, e.g., Zhao et al., Langmuir (1990) 6, 514-516; Zhang et al., Science (1995) 268, 1728-1731; Inoue et al., J. Controlled Release (1998) 51, 221-229 and Kataoka J. Macromol. Sci. Pure Appl. Chem. (1994) A31, 1759-1769. The hydrophobic inner core can also consist of a highly hydrophobic small chain such as an alkyl chain or a diacyllipid (e.g. distearoyl phosphatidyl ethanolamine). The hydrophobic chain can be either attached to one end of a polymer, or randomly distributed within the polymeric structure. The shell usually consists of chains of hydrophilic, non-biodegradable, biocompatible polymers such as poly(ethylene oxide) (PEO) (see Allen et al. Colloids Surf. B: Biointerf. (1999) 16, 3-27 and Kataoka et al. J. Controlled Release (2000) 64, 143-153), poly(N-vinyl-2-pyrrolidone) (PVP) (see Benahmed A et al. Pharm Res (2001) 18, 323-328) or poly(2ethyl-2-oxazoline) (see Lee et al. Macromolecules (1999) 32, 1847-1852). The biodistribution of the carrier is mainly dictated by the nature of the hydrophilic shell. Other polymers such as poly(N-isopropylacrylamide) and poly(alkylacrylic acid) impart temperature or pH sensitivity to the micelles, and could eventually be used to confer bioadhesive properties (see U.S. Pat. No. 5,770,627). Micelles presenting functional groups at their surface for conjugation with a targeting moiety have also been described (See, e.g., Scholz, C. et al., Macromolecules (1995) 28, 7295-7297).
Unimolecular polymeric micelles (UPM) consist of a single macromolecule having an inner core and an outer shell which differ in their hydrophobic and hydrophilic character (see Liu et al. J. Polym. Sci. Part A: Polym. Chem. (1999) 37, 703-711; Liu et al. J. Controlled Release (2000) 65, 121-131). In drug delivery, unimolecular polymeric micelles possess generally a hydrophobic core and a hydrophilic corona. As opposed to supramolecular assemblies, unimolecular micelles are intrinsically stable because they do not show any critical association concentration (CAC per se). Such micelles can solubilize poorly water-soluble compounds and be used as carriers for drug targeting. Since unimolecular micelles do not dissociate upon dilution, compounds are usually released from the inner core by diffusion and/or following the degradation of the polymer backbone (see Liu et al. J. Controlled Release (2000) 68, 167-171). In the case of non biodegradable unimolecular micelles, diffusion is the sole mechanism of drug release.
What is therefore lacking in the prior art is a UPM which is designed to have a more elegant means for release of their contents. More specifically, if a UPM was synthesized with an ionizable inner core, it could be useful in a variety of pharmaceutical applications. For instance, micelles intended to be administered by the oral route can be designed to have a core bearing carboxylic acid groups. Hydrophobic or substantially hydrophobic drugs will be loaded in the inner core under conditions where the latter is protonated. Such micelles should release their contents in the small intestine as the pH rises.
U.S. Pat. No. 5,714,166 discloses dendritic polymer conjugates which are composed of at least one dendrimer in association with at least one unit of a carried material, where the carrier material can be a biological response modifier, have been prepared. The conjugate can also have a target director present, and when it is present then the carried material may be a bioactive agent. Preferred dendritic polymers are dense star polymers, which have been complexed with biological response modifiers. These conjugates and complexes have particularly advantageous properties due to their unique characteristics.
U.S. Pat. No. 6,177,414 is directed toward starburst conjugates which are composed of at least one dendrimer in association with at least one unit of a carried agricultural, pharmaceutical, or other material. These conjugates have particularly advantageous properties due to the unique characteristics of the dendrimer. The carried material is salicylic acid and the dendrimer polymer is a polyamidoamine.
U.S. Pat. No. 6,130,209 relates a key micelle molecule comprising a core molecule and a plurality of branches extending thereform, at least one of said branches including a shank portion extending thereform having a terminal moiety at an end thereof providing a secondary and tertiary structure allowing entrance into a void region of a lock micelle for binding to a complementary acceptor within the void region of the lock unimolecular micelle.
U.S. Pat. No. 5,154,853 cites a method of making a cascade polymer, which includes the steps of: alkylating the branches of a multi-branched core alkyl compound with a terminal alkyne building block including multiple ethereal side chains, and simultaneously reducing the alkyne triple bonds and deprotecting to form a multihydroxyl terminated multi-branched all alkyl polymer.
U.S. Pat. No. 5,206,410 relates the compound 4-[1-(2-cyanoethyl)]-4-[1-(3-(4-chlorobenzyloxy))propyl]-bis-1,7-(4-chloro benzyloxy)heptane. This compound is used as a synthon for the preparation of unimolecular micelles.
U.S. Pat. No. 5,788,989 relates a composition comprising at least one dendrimer and at least one active substance occluded in this dendrimer, wherein the dendrimer has terminal groups, and wherein a sufficient number of terminal groups are blocked with blocking agents whereby active subtances are occluded within dendrimers.
The prior art appears to be silent with regard to the formation of a UPM having an ionizable core for enhanced functionality in a variety of pharmaceutical applications.
The present invention describes the preparation of UPM that bear a hydrophilic shell and a potentially ionizable and relatively hydrophobic core at a determined pH value. The core becomes electrostatically charged as the pH is changed. Such micelles can be made from either biodegradable or non-biodegradable polymers. Loaded drugs can be physically retained in the micelles when the pH of the surrounding medium favors interactions with the core. Upon a change in pH, modification in the ionization state of the core will decrease the interactions between the drug and the inner core and promote the release of the micellar contents. For instance, hydrophobic drugs will be loaded in these micelles under conditions where the core is uncharged. Upon protonation or deprotonation of the core, the increase in polarity will provide the driving force to release the compound.
Accordingly, it is an objective of the instant invention to teach a unimolecular polymeric micelle composition having an ionizable core.
It is yet another objective of the instant invention to provide a process for the controlled release of pharmacological compositions from unimolecular polymeric micelles, wherein said release is triggered by altering the ionization state of the micelle core.
Other objects and advantages of this invention will become apparent from the following description taken in conjunction with the accompanying drawings wherein are set forth, by way of illustration and example, certain embodiments of this invention. The drawings constitute a part of this specification and include exemplary embodiments of the present invention and illustrate various objects and features thereof.